Current therapies against pancreatic cancer (PanCA) are inadequate and limited in efficacy. Therefore there is a huge unmet need for development of novel effective compounds that selectively target tumor cells. Although natural products are well recognized as sources of drugs for various diseases including cancer, very few studies systematically explored the role of natural products for their potential preventive/therapeutic benefit in pancreatic cancer. We have discovered a natural compound called NexrutineR (Nx) isolated from the bark of Phellodendron amurense that inhibits pancreatic cancer cell growth and induces apoptosis and autophagy through production of reactive oxygen species (ROS). Further the observed cytotoxic effects are specific to tumor cells. Nx decreased levels and activity of two key redox-regulated transcription factors that control oncogenic signaling namely NF?B and Stat3 that results in modulation of anti-apoptotic protein FLIP. Based on these observations we postulate that Nx contains novel bioactive compounds with potent anti-pancreatic cancer activity. We will test the hypothesis that Nx and its bioactive compound works through a novel mechanism in which FLIP regulation by two redox-regulated transcription factors (Stat3 and NF?B) leads to modulation of tumor cell specific programmed cell death. This hypothesis will be addressed in following specific aims: 1: Determine the mechanism of cross talk between programmed cell death processes and Nx-induced oxidative stress ina panel of human pancreatic cancer cell lines; 2: Demonstrate that the disruption of cross talk between programmed cell death processes and oxidative stress blocks or delays tumor growth using preclinical animal models of pancreatic cancer; 3: Explore the ability of Palmatine, a bioactive component of Nx recapitulate Nx-induced biological activities using cell culture models; 4: Evaluate that the disruption of cross talk between programmed cell death processes and oxidative stress using Palmatine blocks or delays tumor growth using preclinical animal models of pancreatic cancer. Nx is a promising agent for its anti-tumorigenic activity in cancer cells wit low to no toxicity in normal cells. These studies will provide a rational basis for developing alternative and complementary medicinal strategies for targeting pancreatic cancer. PUBLIC HEALTH RELEVANCE: Incidence and mortality rates for pancreatic cancer (PanCA) are about equal with approximately five people being diagnosed and 4.3 dying from. Current therapies for PanCA are inadequate and limited in efficacy. Furthermore current chemotherapeutic drugs are associated with significant toxicity, undesirable side effects and the emergence of drug resistant phenotype. Therefore there is a huge unmet need for development of novel effective compounds for PanCA patients. NexrutineR (Nx) is an extract from the bark of Phellodendron amurense. It has been used for centuries in Chinese herbal medicine to treat several gastro-intestinal problems. However, its use as an anti-PanCA agent has not been tested. Our preliminary work shows that this compounds works selectively on cancer cells. In this application we will determine its ability to target an aberrant oncogenic pathway (ROS/Stat3/NF?B) leading to the down regulation of anticancer cell death protein called FLIP and induce cancer cells to die. !